Skeletal muscle is a devastating target of chronic kidney disease (CKD) with significant impact on morbidity and mortality through altered metabolism and physical performance. Skeletal muscle plays an important role in glucose homeostasis with a basis in mitochondrial metabolism suggested by prior studies in obese and diabetic patients. Unfortunately the evidence for an association between skeletal muscle dysfunction and insulin resistance in non-diabetic CKD is limited. Several observational studies in community-dwelling elderly patients with CKD have shown decreased physical performance associated with degree of renal dysfunction, but the association of physical performance with insulin resistance and mitochondrial metabolism remains unclear in non-dialysis middle-aged CKD patients. The specific aims of this project are two fold. Our first aim is to examine the determinants of skeletal muscle dysfunction in moderate to advanced non-diabetic CKD both at the whole organ and at the subcellular level. We will be employing standardized physical performance measures along, digital accelerometry assessment of physical activity, and innovative technology through collaboration with the University of Washington Translational Center for Metabolic Imaging using magnetic resonance spectroscopy and optical spectroscopy as a window into skeletal muscle mitochondrial energetics. Our second aim is to examine the relationship between skeletal muscle dysfunction and insulin resistance among persons with chronic kidney disease using gold-standard euglycemic clamp testing. To help successfully complete this project in the planned period, the applicant will have already obtained formal training in advanced epidemiologic methods, including study design, multivariable regression modeling, propensity scoring, and imputation. During his investigation he will gain valuable insight in to muscle mechanics and energetics in collaboration with internationally renowned experts in muscle mechanics and metabolic imaging. He will take courses in muscle physiology and biochemisty and attend seminars on mitochondrial metabolism at the Mitochondrial Metabolism Center sponsored by the Diabetes Endocrine Research Center. This training will advance the applicant towards his goal of becoming an independent investigator specializing in skeletal muscle dysfunction in CKD. A better understanding of the role of skeletal muscle dysfunction in CKD will help link the metabolic consequence of uremia with functional impairment as well as cardiovascular morbidity and mortality. Ultimately, elucidation of the effects of CKD on mitochondrial function will identify a novel mechanism and provide an empiric basis for future large epidemiologic studies and clinical trials targeting mitochondrial dysfunctio in CKD. PUBLIC HEALTH RELEVANCE: Chronic kidney disease (CKD) is a hypercatabolic and inflammatory state with impact on multiple organs sharing many metabolic features of diabetes including insulin resistance. A particularly devastating and underrecognized target of CKD is skeletal muscle. Skeletal muscle dysfunction leads to abnormal glucose homeostasis with a basis in mitochondrial metabolism. Understanding the relationship between uremia of chronic kidney disease and skeletal muscle dysfunction in terms of physical performance, insulin resistance and mitochondrial energetics will help link the metabolic impact of CKD with the functional consequence. This understanding will ultimately identify a novel mechanism and provide an empiric basis for future large epidemiologic studies and clinical trials targeting mitochondrial dysfunction in CKD.